Efficacy, Stability, and Safety Evaluation of New Polyphenolic Xanthones Towards Identification of Bioactive Compounds to Fight Skin Photoaging

Abstract

Antioxidants have long been used in the cosmetic industry to prevent skin photoaging, which is mediated by oxidative stress, making the search for new antioxidant compounds highly desirable in this field. Naturally occurring xanthones are polyphenolic compounds that can be found in microorganisms, fungi, lichens, and some higher plants. This class of polyphenols has a privileged scaffold that grants them several biological activities. We have previously identified simple oxygenated xanthones as promising antioxidants and disclosed as hit, 1,2-dihydroxyxanthone (1). Herein, we synthesized and studied the potential of xanthones with different polyoxygenated patterns as skin antiphotoaging ingredients. In the DPPH antioxidant assay, two newly synthesized derivatives showed IC50 values in the same range as ascorbic acid. The synthesized xanthones were discovered to be excellent tyrosinase inhibitors and weak to moderate collagenase and elastase inhibitors but no activity was revealed against hyaluronidase. Their metal-chelating effect (FeCl3 and CuCl2) as well as their stability at different pH values were characterized to understand their potential to be used as future cosmetic active agents. Among the synthesized polyoxygenated xanthones, 1,2-dihydroxyxanthone (1) was reinforced as the most promising, exhibiting a dual ability to protect the skin against UV damage by combining antioxidant/metal-chelating properties with UV-filter capacity and revealed to be more stable in the pH range that is close to the pH of the skin. Lastly, the phototoxicity of 1,2-dihydroxyxanthone (1) was evaluated in a human keratinocyte cell line and no phototoxicity was observed in the concentration range tested.

From Natural Products to New Synthetic Small Molecules: A Journey through the World of Xanthones

“…This chemical collection of pure xanthones (>95%) was submitted to several screenings to discover their biological activities which allowed to build quantitative structure–activity relationship [(Q)SAR] models and to establish pharmacophores for antitumor [ 48 ], antioxidant [ 49 ], hepatoprotection [ 50 ], antifungal [ 29 , 51 ], antibacterial [ 52 , 53 ], antiobesity [ 54 ], antifouling [ 55 ] activities and/or targets such as monoaminoxidase (MAO) [ 56 ], P-glycoprotein (P-gp) [ 57 , 58 ], protein kinase C (PKC) [ 59 , 60 ], tyrosinase [ 61 ], over these two last decades. Moreover, from these studies several simple oxygenated ( Figure 4 ) or more complex hit compounds emerged that were additionally investigated in many directions, namely for further molecular modifications [ 62 ], for their cellular and molecular mechanism of actions [ 63 , 64 ], for their ADMET properties [ 65 , 66 , 67 ], for chromatographic applications [ 68 , 69 ] and for their incorporation in nanoformulations [ 70 , 71 ].…”

UV Filters: Challenges and Prospects

“…Xanthone derivatives were studied in order to disclose their profiles as future UV filtering molecules. Resende et al (2020) reported three hydroxylated xanthone derivatives ( 162 – 164 ) with promising antioxidant activity and UV filtering characteristics [ 142 ]. Compounds 162 – 164 proved to absorb in the UVB range (280–320 nm).…”

“…Compounds 162 – 164 proved to absorb in the UVB range (280–320 nm). Additionally, xanthone 162 showed a dual ability to protect the skin against UV damage, through DPPH scavenging action and UV-filter capacity, without phototoxicity in the HaCaT keratinocyte cell line [ 142 ]. Popiół et al (2021) also reported novel potential and innovative UV filtering compounds, combining the xanthone scaffold with €-cinnamoyl moiety [ 26 ].…”

“…Compound 166 was revealed to be the most promising, displaying λ c of 381 nm, confirming the ability to absorb both UVA and UVB radiations and with a SPF of 19.69 [ 26 ]. Comparing these two groups of xanthones, the combination of the cinnamoyl and xanthonic moieties allows the correct electronic delocalisation, which improves the UV absorber properties and, because of that, compounds reported by Popiół et al [ 26 ] possess action against UVA and UVB radiation, in contrast to compounds with a simple xanthone scaffold reported by Resende et al [ 142 ].…”

Natural and Artificial Photoprotective Agents

“…Specific requirements for selected applications or the need to fulfill quite stringent consumer needs have guided the search for new and improved sunscreens. Following this trend, Resende and coauthors report the use of new xanthones to protect the skin from photoaging [ 7 ].…”